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An Open-Label Evaluation of Rifaximin in the Treatment of Active Crohn's Disease*

Posted on: Tuesday, 11 October 2005, 03:00 CDT

By Shafran, Ira; Johnson, Lorin K

Key words: Antibiotic - Crohn's disease - Inflammatory bowel disease - Rifaximin

ABSTRACT

Objective: This open-label study was conducted as a preliminary assessment of rifaximin (200 mg TID for 16 weeks) for the treatment of active Crohn's disease in patients (n = 29) with symptoms for at least 3 months before screening and a Crohn's Disease Activity Index (CDAI) score > 220 and < 400.

Results: At the end of month 4, mean + SD CDAI score was reduced by 43% compared with baseline in the intent-to-treat population (n = 29; baseline = 278 51; month 4 = 159 102; p < 0.0001 month 4 versus baseline). A similar pattern of results was observed in the perprotocol population (i.e., patients at least 70% compliant with the treatment regimen and having no protocol violations thought to affect efficacy results; n = 16), in which mean CDAI scores at month 4 were reduced by 41% from a baseline of 262.9 38.2 to 155.6 104.5 (p = 0.0009 month 4 versus baseline). Fifty-nine percent of patients (59%) had a ≥ 70-point improvement in CDAI score beginning with the first assessment at the end of month 1. By the end of the treatment period, 78% of patients had a ≥ 70-point improvement in CDAI score. Clinical remission, defined as CDAI score < 150, was observed at the end of treatment months 1, 2, 3, and 4 in 41%, 56%, 56%, and 59% of patients, respectively. Twenty-three (23) patients completed the 4-month course of rifaximin therapy, and 6 prematurely withdrew. The most common adverse events were abdominal pain, fatigue, and headache.

Conclusion: These data, which are consistent with the possibility that rifaximin may be useful for active Crohn's disease, warrant confirmation in a randomized, double-blind, placebo-controlled trial.

Introduction

The cause of Crohn's disease, which affects up to 480000 individuals in the United States1, remains unknown, but enteric bacteria are implicated in its pathogenesis2-4. In the presence of specific precipitants, genetically susceptible individuals appear to lose enteric immunologic tolerance to commensal flora and develop chronic, uncontrolled inflammation associated with a mucosal immune response to commensal flora. Besides commensal flora, bacterial pathogens may be involved in Crohn's disease, particularly in the onset of the illness and in acute exacerbations5. Inflammatory mediators and other manifestations of the immune response to bacteria cause tissue damage that can culminate in complications, such as obstruction, fistulae, and abscesses, that necessitate surgery, which is required in approximately 8 of 10 patients with Crohn's disease6. In a 2004 report of data from 303 patients, severity and complications of Crohn's disease were directly related to degree of immune reactivity to bacterial antigens. Patients with the greatest immune reactivity to bacterial antigens also had the highest incidence of strictures, internal perforations, and small- bowel surgery7.

Therapy for Crohn's disease is directed primarily at modifying aspects of the enteric inflammatory or immune responses8. In addition, in keeping with the hypothesized role of bacteria in the pathogenesis of Crohn's disease, antibiotics are used in its short- and long-term management. Metronidazole, ciprofloxacin, and clarithromycin have shown evidence of efficacy in clinical studies employing treatment periods of up to 3 years9-15. These data notwithstanding, the role of antibiotics in the management of Crohn's disease remains controversial because of the lack of large, well-controlled clinical trials of antibiotic therapy16-17 and antibiotic limitations such as insufficiently broad spectrum of activity and poor tolerability.

The oral antibiotic rifaximin has several characteristics that may render it suitable for the treatment of Crohn's disease. Rifaximin is a nonabsorbed (< 0.4%) and therefore gut-selective antibiotic with broad-spectrum in vitro activity against Gram- positive and Gram-negative organisms, a tolerability profile comparable to that of placebo in infectious-diarrhea studies, no known drug interactions, and a lack of clinically relevant bacterial resistance18-22. In a rodent model of inflammatory bowel disease, rifaximin prevented intestinal bacterial translocation, inhibited the development of colitis, and expedited healing of established disease23. The open-label study described herein was conducted as a preliminary assessment of rifaximin for the treatment of active Crohn's disease.

Methods

Patients

Adults aged 18-80 years were eligible for the study if they had Crohn's disease confirmed within the year before study entry by endoscopy, surgical pathology, or X-ray; symptoms of active disease at least 3 months before the screening visit; and a Crohn's Disease Activity Index24 (CDAI) score > 220 and < 400 at screening. In addition, patients entering the study on corticosteroids must have been taking them at a stable dose for at least 30 days before screening, and patients entering the study on 6-mercaptopurine or azathioprine must have been taking them at a stable dose for at least 120 days before screening. Females were eligible only if they were not capable of bearing children or, if capable of bearing children, had a negative urine pregnancy test at screening and agreed to use an established, effective method of contraception during the study. Exclusion criteria included use of infliximab within 6 months before screening; the requirement for urgent surgery for peritonitis, abscess, or fistulae; infectious, ischemic, or immunologic diseases (other than Crohn's disease) with gastrointestinal involvement; known moderate to severe fixed symptomatic stenosis of the small or large bowel; uncontrolled hepatic, renal, cardiovascular, or pulmonary disease; and symptoms attributed to short-bowel syndrome. All patients provided written informed consent.

Procedures

The single-center, open-label study, the protocol for which was approved by an institutional review board (Schulman Associates IRB, Inc., Cincinnati, Ohio), consisted of a screening visit followed by a 16-week treatment period during which patients received rifaximin 200 mg TID, a dosage approved for travelers' diarrhea. Patients recorded on daily diary cards the number of liquid/very soft stools, abdominal pain (0 = none to 3 = severe), general well-being (0 = generally well to 4 = terrible), presence of fever > 37.8C, and any use of diphenoxylate, loperamide, codeine, or tincture of opium. At clinic visits conducted at the end of each month of treatment, use of concomitant medications was reviewed; the occurrence of patient- reported or clinician-observed adverse events (defined as any untoward medical occurrences regardless of suspected cause) was recorded; and CDAI score was determined based on clinic examinations and on patient diary data from the 7 days preceding the clinic visit. Scores on the CDAI, which has been shown to be reliable and valid in measuring clinical status in patients with Crohn's disease24, can range from O (no active disease) to 700 (severe disease). Scores ranging from 151 to 400 reflect mild to moderate active disease, and scores of 150 or less reflect remission.

Data analysis

The primary efficacy endpoint was mean change in CDAI score from baseline to the end of the treatment period at month 4. Mean change from baseline in CDAI score was also examined at the end of treatment months 1, 2, and 3. secondary efficacy endpoints, evaluated at the end of each month of treatment, included the percentage of patients with at least a 70-point reduction from baseline in CDAI score (considered to be a meaningful threshold for an adjunctive treatment for Crohn's disease given previous studies of primary therapy for which a 100-point reduction is considered clinically meaningful25,26); the percentage of patients achieving remission, defined as a CDAI score < 150; and mean daily diary ratings of clinical status as defined by total number of liquid/ very soft stools, abdominal pain, general well-being, number of days with fever > 37.8C, and number of days of use of diphenoxylate, loperamide, codeine, or tincture of opium.

Efficacy data were summarized for the intent-to-treat population, defined as all patients receiving treatment and having at least one post-baseline assessment. For the primary endpoint, data were also summarized for the per-protocol population, defined as patients with at least one post-baseline assessment, no protocol violations thought to affect efficacy data, and at least 70% compliance with the study treatment regimen. (Compliance was determined by the investigator on the basis of the amount of remaining drug in study drug cartons, which patients returned to the clinic at each clinic visit.) Missing data were imputed with last-observation-carried- forward (LOCF) values. Differences between baseline and on- treatment values for the primary endpoint were compared with a paired f-test. Differences between baseline and on-treatment values for mean daily diary ratings were compared with Wilcoxon's Signed Rank test. All other efficacy endpoints were summarized descriptively with means and 95% confidence intervals.

The primary tolerability endpoint was the percentage of patients with adverse events, which were categorized according to whether or not the investigator considered them to be at least possibly caused by study m\edication.

Results

Patients

Twenty-nine of the 30 patients who enrolled were included in the intent-to-treat population. One of the 30 patients was not included in the intent-to-treat population because the patient did not meet inclusion/ exclusion criteria. Sixteen of the 30 patients were included in the per-protocol population. Demographics and baseline clinical characteristics are shown in Table 1. Twenty-three patients completed the 4-month course of rifaximin therapy, and 6 prematurely withdrew from the study. The most common reason for premature withdrawal from the study was being lost to follow-up (3 patients) followed by adverse events (2 patients; see Tolerability section below), and lack of efficacy (1 patient). The mean SD number of days on study medication during the 4-month treatment period was 108.1 35.9. Eighty-eight per cent (88%) of patients took study medication for more than 90 days. Concomitant corticosteroids were taken by 8 of the 29 patients (27.6%) in the intent-to-treat population.

Efficacy

Mean SD CDAI score improved versus baseline beginning with the first assessment at the end of month 1 (Figure 1). Mean CDAI scores at month 4 of treatment (primary endpoint) were reduced by 43% from baseline to 159 102 in the intent-to-treat population (p < 0.0001 month 4 versus baseline; Figure 1). A similar pattern of results was observed in the per-protocol population, in which mean CDAI scores at month 4 were reduced by 41% from a baseline of 262.9 38.2 to 155.6 104.5 (p = 0.0009 month 4 versus baseline).

After 1 month of treatment, more than half (59%; 95% confidence interval 39% to 78%) of patients had at least a 70-point reduction from baseline CDAI score (Figure 2). At the end of months 2, 3, and 4 of treatment, 78% to 82% of patients had at least a 70-point decrease from baseline in CDAI score (Figure 2).

Table 1. Demographics, baseline clinical characteristics, and patient disposition (n = 29)

Figure 1. Mean SD CDAI score during 4 months of treatment of active Crohn's disease with rifaximin (n = 29). (The paired t-test was done at Month 4 but not at preceding months)

Figure 2. Percentage of patients (95% confidence interval) with at least a 70-point reduction in CDAl score during 4 months of treatment of active Crohn's disease with rifaximin (n = 29). (No hypothesis testing was undertaken for these data)

Table 2. Mean SD diary scores at baseline and over a 7-day period at the end of 4 months of treatment of active Crohn's disease with rifaximin

At the end of 1 month of treatment with rifaximin, 41% of patients (95% confidence interval 22% to 61%) were in remission as reflected in a CDAI score of less than 150. By month 4 of treatment, 59% of patients (95% confidence interval 39% to 78%) were in remission.

Mean diary scores at month 4 were significantly (p < 0.005) reduced from baseline for several symptoms including number of liquid/very soft stools, abdominal pain and, general well-being (Table 2). Mean diary scores did not significantly differ between month 4 and baseline for number of days with fever > 37.8C and number of days of use of diphenoxylate, loperamide, codeine, or tincture of opium (Table 2). The number of days with fever or with use of the latter medications was low throughout the study.

Tolerability

Adverse events were reported in 21 patients. In 20 of the 21 patients, adverse events were not considered to be caused by study medication. The most common adverse events (regardless of suspected cause) were abdominal pain, fatigue, and headache, each of which was reported in 4 patients. No other adverse event was reported in more than 3 patients.

Discussion

In this study, daily treatment with the nonabsorbed (< 0.4%) oral antibiotic rifaximin was associated with clinical improvement in patients with active Crohn's disease. Moreover, rifaximin administered daily for up to 4 months was well tolerated. In the absence of a placebo control group, the degree to which the improvements might be attributed to rifaximin therapy cannot be definitively determined. Besides the open-label design of the study, patients' use of concomitant medications for Crohn's disease complicates interpretation of the results. Patients were permitted to continue their current medications provided that they had been on a stable dose for a predefined period of time (depending on the medication) before study entry. However, the similar magnitudes of improvement in the primary endpoint in the intent-to-treat population compared with the per-protocol population - which excluded patients who violated protocol by taking concomitant medications that were judged potentially to affect the efficacy results and those not at least 70% compliant with study medication - is consistent with a lack of significant impact of concomitant medication use on the results of the study. Other limitations of the study include the lack of a comparator and the small sample size. Data from this study warrant confirmation in a randomized, doubleblind, placebo-controlled clinical trial.

Acknowledgments

Declaration of interest: The study was supported in part by funds from Salix Pharmaceuticals, Inc.

The authors acknowledge Jane Saiers, PhD, for assistance with writing the manuscript.

* Some of the data described in this manuscript were presented at the 68th Annual Scientific Meeting of the American College of Gastroenterology, October 12-15, 2003, in Baltimore, Maryland

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Ira Shafran(a) and Lorin K. Johnson(b)

a Shafran Gastroenterology Center, Winter Park, FL, USA

b Salix Pharmaceuticals, Inc., Morrisville, NC, USA

Address for correspondence: Ira Shafran, MD, Shafran Gastroenterology Center, 701 West Morse Boulevard, Suite A, Winter Park, FL 32789, USA. Tel.: +1 407 629 8121; email: IRAnita@aol.com

Copyright Librapharm Aug 2005

Source: Current Medical Research and Opinion

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